PROJECT ABSTRACT This K08 proposal will expedite the principal investigator?s progress towards his goal of becoming an independent physician-scientist focused on developing innovative therapies to improve pneumonia outcomes. Candidate: The PI is a physician-scientist at Washington University School of Medicine (WUSM). He completed a fellowship in Pulmonary and Critical Care Medicine and obtained a Master of Science in Clinical Investigation from WUSM, developing expertise at the intersection of innate immunity and airway epithelial cell biology under the mentorship of Dr. John Atkinson, a world authority on the complement system. Under Dr. Atkinson?s mentorship, the PI investigated how intracellular proteins (specifically, complement component C3) modulate cellular responses by mitigating stress-induced cell death. He will leverage the skills gained during his fellowship to further analyze C3 as a cytoprotective therapeutic for reducing pneumonia severity, a major unmet need. Career Development Plan: The PI will execute this proposal under his primary mentor, Dr. Atkinson and co- mentors, Dr. Brody (an expert in airway epithelial cell biology) and Dr. Gelman (an expert in mouse models of lung injury) along with a team of intramural and extramural advisors from diverse fields. All members of the advisory team have considerable experience in nurturing independent investigators. WUSM provides a high- quality environment with excellent facilities, resources and opportunities, as well as a collaborative faculty. This 5-year plan builds on the PI?s prior experience and fills in the gaps in his training, providing him with the tools needed for independence. It includes the following objectives: (1) Master techniques in advanced molecular biology and immunology (i.e., immunophenotyping of mice); (2) Become familiar with designing innovative therapies to improve pneumonia outcomes using preclinical models of lung injury; (3) Present research regularly in diverse venues, actively participate in working groups and collaborate; (4) Enhance mentoring skills; and (5) Publish at least 1 manuscript per year directly related to this proposal. Research Plan: The scientific premise of the proposal is that intracellular C3 in the lung plays a critical protective role in pneumonia, which the PI will test via two Specific Aims. Aim 1 will investigate how C3 promotes airway epithelial cell survival during inflammatory stress in vitro. Aim 2 will interrogate how locally functioning C3 in the lung reduces bacterial pneumonia severity in vivo. The plan is a vehicle for the PI to become facile in: (1) modulating intracellular pathways important for epithelial cell survival; (2) analyzing newly developed conditional knockout mice to ascertain the predominant sources of proteins in the lungs; and (3) developing approaches to deliver or enhance the production of these proteins locally to alleviate lung disease. Completing the Aims will provide the PI with the skills that are readily applicable to other forms of lung injury, and epithelial dysfunction at other barrier surfaces. In short, this K08 award will bolster his scientific career as he becomes an independent investigator who will focus on reducing the burden of pulmonary diseases, in alignment with the NHLBI mission.